6,7-Dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonic acid amides of formula I below, wherein R1 to R3 are as defined herein, have been reported as small molecule inhibitors of the binding of human intercellular adhesion molecules, including ICAM-1, ICAM-2 and ICAM-3, to the Leukointegrins, especially CD18/CD11a. As a result, these small molecules are useful in the treatment of inflammatory and immune cell-mediated diseases (See U.S. Pat. No. 6,492,408, U.S. Pat. No. 6,844,360, WO 2004/041827 A2, U.S. Pat. No. 6,852,748, and WO 2004/041273 A1).

A synthetic route that was used to prepare compounds of formula I (U.S. Pat. No. 6,492,408) is shown in Scheme 1. As illustrated in Scheme 1, reaction of amino-esters of formula II with 3,5-dichlorophenylisothiocyanate provided thiohydantoin III. A solution of triphenylphosphine was treated with azide IV, and the resulting intermediate was reacted with thiohydantoin III to provide guanidine derivative V. Treatment of V with trifluoroacetic acid provided VI. Iodination of VI with N-iodosuccinimide provided VII. Treatment of VII with cyclopentylmagnesium bromide was followed by addition of sulfur dioxide to provide an intermediate magnesium sulfinate salt. Treatment of this intermediate salt with N-chlorosuccinimide provided sulfonyl chloride VIII. Treatment of VIII with the appropriate amine provided the desired compound of formula I or a precursor that could be further modified to provide the desired compound.

An alternate synthesis of intermediate VII illustrated in Scheme 2 was described in U.S. Pat. No. 6,414,161:

As illustrated in Scheme 2, reaction of amino-amide IX with ethyl isocyanatoacetate provided urea X. Dehydration-cyclization of X with carbon tetrachloride, triphenylphosphine and triethylamine produced guanidine XI. Treatment of XI with trimethylaluminum provided lactam XII. Reaction of lactam XII with ethyl chlorophosphate and bis(trimethylsilyl)amide provided phosphate XIII. Iodination of XIII with trimethylsilyl chloride and sodium iodide provided iodo intermediate VII.
Disadvantages of the above two procedures include the use of potentially hazardous reagents such as azide IV (Scheme 1) and the requirement of chromatographic purification, such as purification of XII (Scheme 2). Therefore, the synthetic methods outlined above are not suitable for large scale preparation of compounds of formula I.